[0001] The present invention relates to a pharmaceutical combination comprising compounds
that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs)
and a taxane, and the uses of such a combination, e.g., in proliferative diseases,
e.g., tumors, myelomas and leukemias.
[0002] In spite of numerous treatment options for patients with proliferative diseases,
there remains a need for effective and safe molecularly targeted anti-proliferative
agents. Combination of such exploratory agents with existing therapies sometimes results
in a synergistic interaction and enhanced therapeutic benefit relative to either agent
alone.
Summary of the Invention
[0003] It has now been found that a combination comprising at least one compound that inhibits
the binding of the Smac protein to IAPs and a taxane, e.g., as defined below, has
a beneficial effect on proliferative diseases, e.g., tumors, myelomas and leukemias.
Detailed Description of the Invention
[0004] The invention relates to a pharmaceutical combination which comprises:
- (a) a taxane; and
- (b) a compound (IAP inhibitor) that inhibits the caspase-9 inhibiting properties of
an IAP; and, optionally,
- (c) at least one pharmaceutically acceptable carrier for simultaneous, separate or
sequential use,
in particular, for the treatment of a proliferative disease, especially a solid tumor
disease; a pharmaceutical composition comprising such a combination; the use of such
a combination for the preparation of a medicament for the treatment of a proliferative
disease; a commercial package or product comprising such a combination as a combined
preparation for simultaneous, separate or sequential use; and to a method of treatment
of a warm-blooded animal, especially a human. A greater than additive effect is seen
when compounds (a) and (b) are used in combination.
[0005] Taxanes are microtubule targeting agents that bind to tubulin and block cell division
by interfering with the function of the mitotic spindle. Taxanes represent a first-line
treatment option for metastatic breast, lung, ovarian and digestive cancers and are
commonly used in the adjuvant setting for breast cancer.
[0006] Taxanes include Paclitaxel, marketed as TAXOL and docetaxel, marketed as TAXOTERE.
Other taxanes include vinorelbine and the epothilones, such as epothilone B and patupilone.
[0007] Compounds that inhibit the binding of the Smac protein to IAPs include compounds
of the formula (I):
wherein
R
1 is H, C
1-C
4alkyl, C
1-C
4alkenyl, C
1-C
4alkynyl or C
3-C
10cycloalkyl, which are unsubstituted or substituted;
R
2 is H, C
1-C
4alkyl, C
1-C
4alkenyl, C
1-C
4alkynyl or C
3-C
10cycloalkyl, which are unsubstituted or substituted;
R
3 is H, -CF
3, -C
2F
5, C
1-C
4alkyl, C
1-C
4alkenyl, C
1-C
4alkynyl, -CH
2-Z, wherein Z is H, -OH, F, Cl, -CH
3, -CF
3, -CH
2Cl, -CH
2F or -CH
2OH, or
R
2 and R
3, together with the nitrogen, form a het ring;
R
4 is C
1-C
16straight- or branched-alkyl, C
1-C
16alkenyl, C
1-C
16alkynyl or -C
3-C
10cycloalkyl, -(CH
2)
1-6Z
1, -(CH
2)
0-6aryl and -(CH
2)
0-6het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted,
wherein
Z
1 is -N(R
8)-C(O)-C
1-C
10alkyl, -N(R
8)-C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -N(R
8)-C(O)-(CH
2)
0-6phenyl, -N(R
8)-C(O)-(CH
2)
1-6het, -C(O)-N(R
9)(R
10), -C(O)-O-C
1-C
10alkyl, -C(O)-O-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-O-(CH
2)
0-6phenyl, -C(O)-O-(CH
2)
1-6het, -O-C(O)C
1-C
10alkyl, -O-C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -O-C(O)-(CH
2)
0-6phenyl, -O-C(O)-(CH
2)
1-6het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; and
het is a 5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from
N, O and S, or an 8- to 12-membered fused ring system including at least one 5- to
7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O,
and S, which heterocyclic ring or fused ring system is unsubstituted or substituted
on a carbon or nitrogen atom,
wherein
R
8 is H, -CH
3, -CF
3, -CH
2OH or -CH
2Cl;
R
9 and R
10 are each independently H, C
1-C
4alkyl, C
3-C
7cycloalkyl, -(CH
2)
1-6C
3-C
7cycloalkyl, -(CH
2)
0-6phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or
R
9 and R
10, together with the nitrogen, form het;
R
5 is H, C
1-C
10alkyl, aryl, phenyl, C
3-C
7cycloalkyl, -(CH
2)
1-6C
3-C
7cycloalkyl, -C
1-C
10alkylaryl, -(CH
2)
0-6C
3-C
7cycloalkyl-(CH
2)
0-6phenyl, -(CH
2)
0-4CH-((CH
2)
1-4phenyl)
2, -(CH
2)
0-6CH(phenyl)
2, -indanyl, -C(O)-C
1-C
10alkyl, -C(O)-(CH
2)
1-6C
3-C
7-cycloalkyl, -C(O)-(CH
2)
0-6phenyl, -(CH
2)
0-6C(O)-phenyl, -(CH
2)
0-6het, -C(O)-(CH
2)
1-6het, or
R
5 is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents
are unsubstituted or substituted; and
U is as shown in formula (II):
wherein
n is 0-5;
X is -CH or N;
Ra and Rb are independently an O, S or N atom or C
0-C
8alkyl, wherein one or more of the carbon atoms in the alkyl chain may be replaced
by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted
or substituted;
Rd is selected from:
- (a) -Re - Q - (Rf)p(Rg)q; or
- (b) Ar1-D- Ar2,
wherein
p and q are independently 0 or 1;
Re is C1-C8alkyl or alkylidene and
Re which may be unsubstituted or substituted;
Q is N, O, S, S(O), or S(O)2;
Ar1 and Ar2 are substituted or unsubstituted aryl or het;
Rf and Rg are each independently H, -C1-C10alkyl, C1-C10alkylaryl, -OH, -O-C1-C10alkyl, -(CH2)0-6C3-C7cycloalkyl, -O-(CH2)0-6aryl, phenyl, aryl, phenyl-phenyl, -(CH2)1-6het, -O-(CH2)1-6het, -OR11, -C(O)-R11, -C(O)-N(R11)(R12), -N(R11)(R12), -S-R11, -S(O)-R11, -S(O)2-R11, -S(O)2-NR11R12, -NR11-S(O)2-R12, S-C1-C10alkyl, aryl-C1-C4alkyl, het-C1-C4-alkyl, wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted,
-SO2-C1-C2alkyl, -SO2-C1-C2alkylphenyl, -O-C1-C4alkyl, or
Rg and Rf form a ring selected from het or aryl;
D is -CO-, -C(O)-C1-C7alkylene or arylene, -CF2-, -O-, -S(O)r, where r is 0-2, 1,3-dioaxolane or C1-C7alkyl-OH, where alkyl, alkylene or arylene may be unsubstituted or substituted with
one or more halogens, OH, -O-C1-C6alkyl, -S-C1-C6alkyl or -CF3, or
D is -N(Rh), wherein Rh is H, C1-C7alkyl (unsubstituted or substituted), aryl, -O(C1-C7cycloalkyl) (unsubstituted or substituted), C(O)-C1-C10alkyl, C(O)-Co-C10alkyl-aryl, C-O-C1-C10alkyl, C-O-Co-C10alkyl-aryl or SO2-C1-C10-alkyl, SO2-(Co-C10-alkylaryl);
Rc is H, or
Rc and Rd may together form a cycloalkyl or het, where if Rd and Rc form a cycloalkyl
or het, R5 is attached to the formed ring at a C or N atom;
R6, R7, R'6 and R'7 are each independently H, -C1-C10alkyl, -C1-C10alkoxy, aryl-C1-C10alkoxy, -OH, -O-C1-C10alkyl, -(CH2)0-6C3-C7cycloalkyl, -O-(CH2)0-6aryl, phenyl, -(CH2)1-6het, -O-(CH2)1-6het, -OR11, -C(O)-R11, -C(O)-N(R11)(R12), -N(R11)(R12), -S-R11, -S(O)-R11, -S(O)2-R11, -S(O)2-NR11R12, -NR11-S(O)2-R12, wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted; and R6, R7, R'6 and R'7 can be united to form a ring system,
wherein
R11 and R12 are independently H, C1-C10alkyl, -(CH2)0-6C3-C7cycloalkyl, -(CH2)0-6(CH)0-1(aryl)1-2, -C(O)-C1-C10alkyl, -C(O)-(CH2)1-6C3-C7cycloalkyl, -C(O)-O-(CH2)0-6aryl, -C(O)-(CH2)0-6O-fluorenyl, -C(O)-NH-(CH2)0-6aryl, -C(O)-(CH2)0-6aryl, -C(O)-(CH2)1-6het, -C(S)-C1-C10alkyl, -C(S)-(CH2)1-6C3-C7cycloalkyl, -C(S)-O-(CH2)0-6aryl, -C(S)-(CH2)0-6O-fluorenyl, -C(S)-NH-(CH2)0-6aryl, -C(S)-(CH2)0-6aryl, -C(S)-(CH2)1-6het, wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted, or
R11 and R12 are a substituent that facilitates transport of the molecule across a cell membrane,
or
R11 and R12, together with the nitrogen atom, form het,
wherein
the alkyl substituents of R11 and R12 may be unsubstituted or substituted by one or more substituents selected from C1-C10alkyl, halogen, OH, -O-C1-C6alkyl, -S-C1-C6alkyl or -CF3;
substituted cycloalkyl substituents of R11 and R12 are substituted by one or more substituents selected from a C1-C10alkene, C1-C6alkyl, halogen, OH, -O-C1-C6alkyl, -S-C1-C6alkyl or -CF3; and
substituted phenyl or aryl of R11 and R12 are substituted by one or more substituents selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, nitro, -CN, -O-C(O)-C1-C4alkyl and -C(O)-O-C1-C4aryl;
or pharmaceutically acceptable salts thereof.
[0008] The general terms used hereinbefore and hereinafter preferably have within the context
of this disclosure the following meanings, unless otherwise indicated:
"Aryl" is an aromatic radical having 6-14 carbon atoms, which may be fused or unfused,
and which is unsubstituted or substituted by 1 or more, preferably 1 or 2 substituents,
wherein the substituents are as described below. Preferred "aryl" is phenyl, naphthyl
or indanyl.
"Het" refers to heteroaryl and heterocyclic rings and fused rings containing aromatic
and non-aromatic heterocyclic rings. "Het" is a 5- to 7-membered heterocyclic ring
containing 1-4 heteroatoms selected from N, O and S, or an 8- to 12-membered fused
ring system including at least one 5- to 7-membered heterocyclic ring containing 1,
2 or 3 heteroatoms selected from N, O and S. Suitable het substituents include unsubstituted
and substituted pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl,
tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, 1,4-oxathiapane,
furyl, thienyl, pyrrole, pyrazole, triazole, 1,2,3-triazole, tetrazolyl, oxadiazole,
thiophene, imidazol, pyrrolidine, pyrrolidone, thiazole, oxazole, pyridine, pyrimidine,
isoxazolyl, pyrazine, quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine,
indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline and
the like. The het substituents are unsubstituted or substituted on a carbon atom by
halogen, especially fluorine or chlorine; hydroxy; C1-C4alkyl, such as methyl and ethyl; C1-C4alkoxy, especially methoxy and ethoxy; nitro; -O-C(O)-C1-C4alkyl or -C(O)-O-C1-C4alkyl or on a nitrogen by C1-C4alkyl, especially methyl or ethyl; -O-C(O)-C1-C4alkyl or -C(O)-O-C1-C4alkyl, such as carbomethoxy or carboethoxy.
[0009] When two substituents together with a commonly bound nitrogen are het, it is understood
that the resulting heterocyclic ring is a nitrogen-containing ring, such as aziridine,
azetidine, azole, piperidine, piperazine, morphiline, pyrrole, pyrazole, thiazole,
oxazole, pyridine, pyrimidine, isoxazolyl and the like.
[0010] Halogen is fluorine, chlorine, bromine or iodine, especially fluorine and chlorine.
[0011] Unless otherwise specified "alkyl" includes straight- or branched-chain alkyl, such
as methyl, ethyl,
n-propyl, isopropyl,
n-butyl,
sec-butyl,
tert-butyl,
n-pentyl and branched pentyl,
n-hexyl and branched hexyl and the like.
[0012] A "cycloalkyl" group means C
3-C
10cycloalkyl having 3- to 8-ring carbon atoms and may be, e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferably, cycloalkyl is cycloheptyl.
The cycloalkyl group may be unsubstituted or substituted with any of the substituents
defined below, preferably halo, hydroxy or C
1-C
4alkyl, such as methyl.
[0013] The amino acid residues include a residue of a standard amino acid, such as alanine,
arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine,
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,
threonine, tryptophan, tyrosine and valine. The amino acid residues also include the
side chains of uncommon and modified amino acids. Uncommon and modified amino acids
are known to those of skill in the art [see, e.g.,
Fields, Tiam and Barany, Synthetic Peptides A Users Guide, University of Wisconsin
Biochemistry Center, Chapter 3, (1992)] and include amino acids, such as 4-hydroxyproline, 5-hydroxylysine, desmosine,
beta (β)-alanine, alpha (α)-, gamma (γ)- and β-aminobutric acid, homocysteine, homoserine,
citrulline, ornithine, 2- or 3-amino adipic acid, 6-aminocaproic acid, 2- or 3-aminoisobutric
acid, 2,3-diaminopropionic acid, diphenylalanine, hydroxyproline and the like. If
the side chain of the amino acid residue contains a derivatizable group, such as COOH,
-OH or amino, the side chain may be derivatized by a substituent that reacts with
the derivatizable group. For example, acidic amino acids, like aspartic and glutamic
acid, or hydroxy substituted side chains, like those of serine or threonine, may be
derivatized to form an ester, or amino side chains may form amide or alkylamino derivatives.
In particular, the derivative may be a substituent that facilitates transport across
a cell membrane. In addition, any carboxylic acid group in the amino acid residue,
e.g., an α-carboxylic acid group, may be derivatized as discussed above to form an
ester or amide.
[0014] Substituents that facilitate transport of the molecule across a cell membrane are
known to those of skill in the medicinal chemistry arts. See, e.g.,
Gangewar et al., Drug Dis Today, Vol. 2, pp. 148-155 (1997); and
Bundgaard and Moss, Pharma Res, Vol. 7, p. 885 (1990). Generally, such substituents are lipophillic substituents. Such lipophillic substituents
include a C
6-C
30alkyl, which is saturated, monounsaturated, polyunsaturated, including methylene-interrupted
polyene, phenyl, phenyl which substituted by one or two C
1-C
8alkyl groups, C
5-C
9cycloalkyl, C
5-C
9cycloalkyl, which is substituted by one or two C
1-C
8alkyl groups, -X
1-phenyl, -X
1-phenyl, which is substituted in the phenyl ring by one or two C
1-C
8alkyl groups, X
1-C
5-C
9cycloalkyl or X
1-C
5-C
9cycloalkyl, which is substituted by one or two C
1-C
8alkyl groups, where X
1 is C
1-C
24alkyl, which is saturated, mono-unsaturated or polyunsaturated and straight- or branched-chain.
[0015] Unsubstituted is intended to mean that hydrogen is the only substituent.
[0016] Any of the above defined aryl, het, alkyl, cycloalkyl, or heterocyclic groups may
be unsubstituted or independently substituted by up to 4, preferably 1, 2 or 3 substituents,
selected from the group consisting of: halo, such as Cl or Br; hydroxy; lower alkyl,
such as C
1-C
3lower alkyl; lower alkyl, which may be substituted with any of the substituents defined
herein; lower alkenyl; lower alkynyl; lower alkanoyl; alkoxy, such as methoxy, aryl,
such as phenyl or benzyl; substituted aryl, such as fluoro phenyl or methoxy phenyl;
amino; mono-or di-substituted amino; amino lower alkyl, such as dimethylamino; acetyl
amino; amino lower alkoxy, such as ethoxyamine; nitro; cyano; cyano lower alkyl; carboxy;
esterified carboxy, such as lower alkoxy carbonyl, e.g., methoxy carbonyl;
n-propoxy carbonyl or iso-propoxy carbonyl; alkanoyl; benzoyl; carbamoyl;
N-mono- or
N,N-di-substituted carbamoyl; carbamates; alkyl carbamic acid esters; amidino; guanidine;
urea; ureido; mercapto; sulfo; lower alkylthio; sulfoamino; sulfonamide; benzosulfonamide;
sulfonate; sulfanyl lower alkyl, such as methyl sulfanyl; sulfoamino; substituted
or unsubstituted sulfonamide, such as benzo sulfonamide; substituted or unsubstituted
sulfonate, such as chloro-phenyl sulfonate; lower alkylsulfinyl; phenylsulfinyl; phenyl-lower
alkylsulfinyl; alkylphenylsulfinyl; lower alkanesulfonyl; phenylsulfonyl; phenyl-lower
alkylsulfonyl; alkylphenylsulfonyl; halogen-lower alkylmercapto; halogen-lower alkylsulfonyl,
such as especially trifluoromethane sulfonyl; phosphono (-P(=O)(OH)
2); hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl; substituted urea,
such as 3-trifluoro-methyl-phenyl urea; alkyl carbamic acid ester or carbamates, such
as ethyl-
N-phenyl-carbamate or -NR
4R
5,
wherein
R
4 and R
5 can be the same or different and are independently H; lower alkyl, e.g., methyl,
ethyl or propyl, or
R
4 and R
5, together with the N atom, form a 3- to 8-membered heterocyclic ring containing 1-4
nitrogen, oxygen or sulfur atoms, e.g., piperazinyl, pyrazinyl, lower alkyl-piperazinyl,
pyridyl, indolyl, thiophenyl, thiazolyl,
n-methyl piperazinyl, benzothiophenyl, pyrrolidinyl, piperidino or imidazolinyl, where
the heterocyclic ring may be substituted with any of the substituents defined herein.
[0017] Preferably, the above-mentioned alkyl, cycloalkyl, aryl or het groups may be substituted
by halogen, carbonyl, thiol, S(O), S(O
2), -OH, -SH, -OCH
3, -SCH
3, -CN, -SCN or nitro.
[0018] Where the plural form is used for compounds, salts, pharmaceutical preparations,
diseases and the like, this is intended to mean also a single compound, salt or the
like.
[0019] It will be apparent to one of skill in the art when a compound of the invention can
exist as a salt form, especially as an acid addition salt or a base addition salt.
When a compound can exist in a salt form, such salt forms are included within the
scope of the invention. Although any salt form may be useful in chemical manipulations,
such as purification procedures, only pharmaceutically acceptable salts are useful
for pharmaceutically products.
[0020] Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable
base addition salts and acid addition salts, e.g., metal salts, such as alkali and
alkaline earth metal salts; ammonium salts; organic amine addition salts; amino acid
addition salts; and sulfonate salts. Acid addition salts include inorganic acid addition,
salts such as hydrochloride, sulfate and phosphate; and organic acid addition salts,
such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate
and lactate. Examples of metal salts are alkali metal salts, such as lithium salt,
sodium salt and potassium salt; alkaline earth metal salts, such as magnesium salt
and calcium salt, aluminum salt and zinc salt. Examples of ammonium salts are ammonium
salt and tetramethylammonium salt. Examples of organic amine addition salts are salts
with morpholine and piperidine. Examples of amino acid addition salts are salts with
glycine, phenylalanine, glutamic acid and lysine. Sulfonate salts include mesylate,
tosylate and benzene sulfonic acid salts.
[0021] In view of the close relationship between the compounds in free form and those in
the form of their salts, including those salts that can be used as intermediates,
e.g., in the purification or identification of the compounds, tautomers or tautomeric
mixtures and their salts, any reference to the compounds hereinbefore and hereinafter
especially the compounds of the formula (I), is to be understood as referring also
to the corresponding tautomers of these compounds, especially of compounds of the
formula (I), tautomeric mixtures of these compounds, especially of compounds of the
formula (I), or salts of any of these, as appropriate and expedient and if not mentioned
otherwise.
[0022] Any asymmetric carbon atom may be present in the (
R)-
, (
S)- or (
R,
S)-configuration, preferably in the (
R)- or (
S)-configuration. Substituents at a ring at atoms with saturated bonds may, if possible,
be present in
cis (=Z-) or
trans (= E-) form. The compounds may thus be present as mixtures of isomers or preferably
as pure isomers, preferably as enantiomer-pure diastereomers or pure enantiomers.
[0023] Compounds within the scope of formula (I) and the process for their manufacture are
disclosed in
WO 05/097791 published on October 20, 2005, which is hereby incorporated into the present application by reference. A preferred
compounds within the scope of formula (I) is
N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-
c]pyridin-1-yl-ethyl]-2-methylamino-propionamide of formula (III):
[0024] Additional compounds that inhibit the binding of the Smac protein to IAPs include
compounds of the formula (IV):
wherein
R
1 is H;
R
2 is H, C
1-C
4alkyl, which is unsubstituted or substituted by one or more substituents selected
from halogen, -OH, -SH, -OCH
3, -SCH
3, -CN, -SCN and nitro;
R
3 is H, -CF
3, -C
2F
5, -CH
2-Z, wherein Z is H, -OH, F, Cl, -CH
3, -CF
3, -CH
2Cl, -CH
2F or -CH
2OH, or
R
2 and R
3, together with the nitrogen, form a C
3-C
6heteroaliphatic ring;
R
4 is C
1-C
16straight-chain alkyl, C
3-C
10branched-chain alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -(CH
2)
1-6Z
1, -(CH
2)
0-6phenyl and -(CH
2)
0-6het, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or substituted,
wherein
Z
1 is -N(R
9)-C(O)-C
1-C
10alkyl, -N(R
9)-C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -N(R
9)-C(O)-(CH
2)
0-6phenyl, -N(R
9)-C(O)-(CH
2)
1-6het, -C(O)-N(R
10)(R
11), -C(O)-O-C
1-C
10alkyl, -C(O)-O-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-O-(CH
2)
0-6phenyl, -C(O)-O-(CH
2)
1-6het, -O-C(O)-C
1-C
10alkyl, -O-C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -O-C(O)-(CH
2)
0-6phenyl, -O-C(O)-(CH
2)
1-6het, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or substituted,
wherein
R
9 is H, -CH
3, -CF
3, -CH
2OH or CH
2Cl;
R
10 and R
11 are each independently H, C
1-C
4alkyl, C
3-C
7cycloalkyl, -(CH
2)
1-6C
3-C
7cycloalkyl, -(CH
2)
0-6phenyl, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or
substituted, or
R
10 and R
11, together with the nitrogen, are het;
het is a 5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected
from N, O and S, or an 8- to 12-membered fused ring system including at least one
5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from
N, O and S, which heterocyclic ring or fused ring system is unsubstituted or substituted
on a carbon atom by halogen, hydroxy, C
1-C
4alkyl, C
1-C
4alkoxy, nitro, -O-C(O)-C
1-C
4alkyl or -C(O)-O-C
1-C
4alkyl or on a nitrogen by C
1-C
4alkyl, -O-C(O)-C
1-C
4alkyl or -C(O)-O-C
1-C
4alkyl;
X is CH or N;
R
5 is H, C
1-C
10alkyl, C
3-C
7cycloalkyl, -(CH
2)
1-6C
3-C
7cycloalkyl, -C
1-C
10alkyl-aryl, -(CH
2)
0-6C
3-C
7cycloalkyl-(CH
2)
0-6phenyl, -(CH
2)
0-4CH-((CH
2)
1-4phenyl)
2, -(CH
2)
0-6CH(phenyl)
2, -C(O)-C
1-C
10alkyl, -C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-(CH
2)
0-6phenyl, -(CH
2)
1-6het, -C(O)-(CH
2)
1-6het, or
R
5 is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents
are unsubstituted or substituted;
R
6 is H, methyl, ethyl, -CF
3, -CH
2OH or -CH
2Cl, or
R
5 and R
6, together with the nitrogen, are het;
R
7 and R
8 are cis relative to the acyl substituent at the one position of the ring and are
each independently H, -C
1-C
10alkyl, -OH, -O-C
1-C
10alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -O-(CH
2)
0-6aryl, phenyl, -(CH
2)
1-6het, -O-(CH
2)
1-6het, -N(R
12)(R
13), -S-R
12, -S(O)-R
12, -S(O)
2-R
12, -S(O)
2-NR
12R
13, wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted,
wherein
R
12 and R
13 are independently H, C
1-C
10alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -(CH
2)
0-6(CH)
0-1(aryl)
1-2, -C(O)-C
1-C
10alkyl, -C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-O-(CH
2)
0-6aryl, -C(O)-(CH
2)
0-6O-fluorenyl, -C(O)-NH-(CH
2)
0-6aryl, -C(O)-(CH
2)
0-6aryl, -C(O)-(CH
2)
1-6het, wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted;
or a substituent that facilitates transport of the molecule across a cell membrane,
or
R
12 and R
13, together with the nitrogen, are het; and
aryl is phenyl or naphthyl which is unsubstituted or substituted;
n is 0, 1 or 2;
substituted alkyl substituents are substituted by one or more substituents selected
from a double bond, halogen, OH, -O-C
1-C
6alkyl, -S-C
1-C
6alkyl and -CF
3;
substituted cycloalkyl substituents are substituted by one or more substituents selected
from a double bond, C
1-C
6alkyl, halogen, OH, -O-C
1-C
6alkyl, -S-C
1-C
6alkyl and - CF
3; and
substituted phenyl or aryl are substituted by one or more substituents selected from
halogen, hydroxy, C
1-C
4alkyl, C
1-C
4alkoxy, nitro, -CN, -O-C(O)-C
1-C
4alkyl and -C(O)-O-C
1-C
4alkyl.
[0025] Unsubstituted is intended to mean that hydrogen is the only substituent.
[0026] Halogen is fluorine, chlorine, bromine or iodine, especially fluorine and chlorine.
[0027] Unless otherwise specified alkyl substituents include straight- or branched-chain
alkyl, such as methyl, ethyl,
n-propyl, isopropyl,
n-butyl,
sec-butyl,
tert-butyl,
n-pentyl and branched pentyl,
n-hexyl and branched hexyl and the like.
[0028] Cycloalkyl substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and cycloheptyl.
[0029] Compounds within the scope of formula (VIII) and the process for their manufacture
are disclosed in
WO 04/005284, which is hereby incorporated into the present application by reference.
[0030] In each case where citations of patent applications are given above, the subject
matter relating to the compounds is hereby incorporated into the present application
by reference. Comprised are likewise the pharmaceutically acceptable salts thereof,
the corresponding racemates, diastereoisomers, enantiomers, tautomers, as well as
the corresponding crystal modifications of above disclosed compounds where present,
e.g., solvates, hydrates and polymorphs, which are disclosed therein. The compounds
used as active ingredients in the combinations of the invention can be prepared and
administered as described in the cited documents, respectively. Also within the scope
of this invention is the combination of more than two separate active ingredients
as set forth above, i.e., a pharmaceutical combination within the scope of this invention
could include three active ingredients or more.
[0031] In accordance with the particular findings of the present invention, there is provided:
- 1. A pharmaceutical combination comprising:
- a) a compound that inhibit the binding of the Smac protein to IAPs of formula (I)
or (IV); and
- b) at least one taxane.
- 2. A method for treating or preventing proliferative disease in a subject in need
thereof, comprising co-administration to said subject, e.g., concomitantly or in sequence,
of a therapeutically effective amount of a compound that inhibit the binding of the
Smac protein to IAPs of formula (I) or (VIII) and a taxane. Examples of proliferative
diseases include, e.g., tumors, leukemias and myelomas.
- 3. A pharmaceutical combination as defined under 1) above, e.g.. for use in a method
as defined under 2) above.
- 4. A pharmaceutical combination as defined under 1) above for use in the preparation
of a medicament for use in a method as defined under 2) above.
[0032] Utility of the combination of the invention in a method as hereinabove specified,
may be demonstrated in animal test methods, as well as in clinic, e.g., in accordance
with the methods hereinafter described.
[0033] It has now surprisingly been found that the combination of a compounds that inhibit
the binding of the Smac protein to IAPs and a taxane possesses therapeutic properties,
which render it particularly useful as a treatment for proliferative diseases.
[0034] In another embodiment, the instant invention provides a method for treating proliferative
diseases comprising administering to a mammal in need of such treatment a therapeutically
effective amount of the combination of compounds that inhibit the binding of the Smac
protein to IAPs and a taxane or pharmaceutically acceptable salts or prodrugs thereof.
[0035] In another embodiment, compounds that inhibit the binding of the Smac protein to
IAPs are selected from compounds of formulae (I) and (IV) as defined above.
[0036] Preferably, the instant invention provides a method for treating mammals, especially
humans, suffering from proliferative diseases comprising administering to a mammal
in need of such treatment an inhibiting amount of the combination of compounds that
inhibit the binding of the Smac protein to IAPs and a taxane or pharmaceutically acceptable
salts thereof.
[0037] In the present description, the term "treatment" includes both prophylactic or preventative
treatment, as well as curative or disease suppressive treatment, including treatment
of patients at risk of contracting the disease or suspected to have contracted the
disease, as well as ill patients. This term further includes the treatment for the
delay of progression of the disease.
[0038] The term "curative:, as used herein, means efficacy in treating ongoing episodes
involving proliferative diseases.
[0039] The term "prophylactic" means the prevention of the onset or recurrence of diseases
involving proliferative diseases.
[0040] The term "delay of progression", as used herein, means administration of the active
compound to patients being in a pre-stage or in an early phase of the disease to be
treated, in which patients, e.g. a pre-form of the corresponding disease is diagnosed
or which patients are in a condition, e.g., during a medical treatment or a condition
resulting from an accident, under which it is likely that a corresponding disease
will develop.
[0041] This unforeseeable range of properties means that the use of the combination of a
compounds that inhibit the binding of the Smac protein to IAPs and taxanes are of
particular interest for the manufacture of a medicament for the treatment of proliferative
diseases.
[0042] To demonstrate that the combination of a compounds that inhibit the binding of the
Smac protein to IAPs and taxanes is particularly suitable for the treatment of proliferative
diseases with good therapeutic margin and other advantages, clinical trials can be
carried out in a manner known to the skilled person.
A. Combined Treatment
[0043] A combination which comprises:
- (a) a taxane; and
- (b) an IAP inhibitor, in which the active ingredients are present in each case in
free form or in the form of a pharmaceutically acceptable salt; and, optionally, at
least one pharmaceutically acceptable carrier,
will be referred to hereinafter as a COMBINATION OF THE INVENTION.
[0044] Suitable clinical studies are, e.g., open-label, dose escalation studies in patients
with proliferative diseases. Such studies prove in particular the synergism of the
active ingredients of the COMBINATION OF THE INVENTION. The beneficial effects can
be determined directly through the results of these studies which are known as such
to a person skilled in the art. Such studies are, in particular, suitable to compare
the effects of a monotherapy using the active ingredients and a COMBINATION OF THE
INVENTION. Preferably, the dose of:
- agent (a) is escalated until the Maximum Tolerated Dosage is reached; and
- agent (b) is administered with a fixed dose.
[0045] Alternatively, the agent (a) is administered in a fixed dose and the dose of agent
(b) is escalated. Each patient receives doses of the agent (a) either daily or intermittent.
The efficacy of the treatment can be determined in such studies, e.g., after 12, 18
or 24 weeks by evaluation of symptom scores every 6 weeks.
[0046] The administration of a pharmaceutical COMBINATION OF THE INVENTION results not only
in a beneficial effect, e.g., a synergistic therapeutic effect, e.g., with regard
to alleviating, delaying progression of or inhibiting the symptoms, but also in further
surprising beneficial effects, e.g., fewer side effects, an improved quality of life
or a decreased morbidity, compared with a monotherapy applying only one of the pharmaceutically
active ingredients used in the combination of the invention.
[0047] A further benefit is that lower doses of the active ingredients of the COMBINATION
OF THE INVENTION can be used, e.g., that the dosages need not only often be smaller
but are also applied less frequently, which may diminish the incidence or severity
of side effects. This is in accordance with the desires and requirements of the patients
to be treated.
[0048] The terms "co-administration" or "combined administration" or the like as utilized
herein are meant to encompass administration of the selected therapeutic agents to
a single patient, and are intended to include treatment regimens in which the agents
are not necessarily administered by the same route of administration or at the same
time.
[0049] It is one objective of this invention to provide a pharmaceutical composition comprising
a quantity, which is jointly therapeutically effective at targeting or preventing
proliferative diseases a COMBINATION OF THE INVENTION. In this composition, agents
(a) and (b) may be administered together, one after the other or separately in one
combined unit dosage form or in two separate unit dosage forms. The unit dosage form
may also be a fixed combination.
[0050] The pharmaceutical compositions for separate administration of agents (a) and (b)
or for the administration in a fixed combination, i.e., a single galenical composition
comprising at least two combination partners (a) and (b), according to the invention
may be prepared in a manner known
per se and are those suitable for enteral, such as oral or rectal, and parenteral administration
to mammals (warm-blooded animals), including humans, comprising a therapeutically
effective amount of at least one pharmacologically active combination partner alone,
e.g., as indicated above, or in combination with one or more pharmaceutically acceptable
carriers or diluents, especially suitable for enteral or parenteral application.
[0051] Suitable pharmaceutical compositions contain, for example, from about 0.1% to about
99.9%, preferably from about 1% to about 60%, of the active ingredient(s). Pharmaceutical
preparations for the combination therapy for enteral or parenteral administration
are, e.g., those in unit dosage forms, such as sugar-coated tablets, tablets, capsules
or suppositories, or ampoules. If not indicated otherwise, these are prepared in a
manner known
per se, e.g., by means of conventional mixing, granulating, sugar-coating, dissolving or
lyophilizing processes. It will be appreciated that the unit content of a combination
partner contained in an individual dose of each dosage form need not in itself constitute
an effective amount since the necessary effective amount can be reached by administration
of a plurality of dosage units.
[0052] In particular, a therapeutically effective amount of each of the combination partner
of the combination of the invention may be administered simultaneously or sequentially
and in any order, and the components may be administered separately or as a fixed
combination. For example, the method of preventing or treating proliferative diseases
according to the invention may comprise:
- (i) administration of the first agent (a) in free or pharmaceutically acceptable salt
form; and
- (ii) administration of an agent (b) in free or pharmaceutically acceptable salt form,
simultaneously or sequentially in any order, in jointly therapeutically effective
amounts, preferably in synergistically effective amounts, e.g., in daily or intermittently
dosages corresponding to the amounts described herein. The individual combination
partners of the combination of the invention may be administered separately at different
times during the course of therapy or concurrently in divided or single combination
forms. Furthermore, the term administering also encompasses the use of a pro-drug
of a combination partner that convert
in vivo to the combination partner as such. The instant invention is therefore to be understood
as embracing all such regimens of simultaneous or alternating treatment and the term
"administering" is to be interpreted accordingly.
[0053] The term "a combined preparation", as used herein, defines especially a "kit of parts"
in the sense that the combination partners (a) and (b) as defined above can be dosed
independently or by use of different fixed combinations with distinguished amounts
of the combination partners (a) and (b), i.e., simultaneously or at different time
points. The parts of the kit of parts can then, e.g., be administered simultaneously
or chronologically staggered, that is at different time points and with equal or different
time intervals for any part of the kit of parts. The ratio of the total amounts of
the combination partner (a) to the combination partner (b) to be administered in the
combined preparation can be varied, e.g., in order to cope with the needs of a patient
sub-population to be treated or the needs of the single.
[0054] The effective dosage of each of the combination partners employed in the combination
of the invention may vary depending on the particular compound or pharmaceutical composition
employed, the mode of administration, the condition being treated, the severity of
the condition being treated. Thus, the dosage regimen of the combination of the invention
is selected in accordance with a variety of factors including the route of administration
and the renal and hepatic function of the patient. A clinician or physician of ordinary
skill can readily determine and prescribe the effective amount of the single active
ingredients required to alleviate, counter or arrest the progress of the condition.
Optimal precision in achieving concentration of the active ingredients within the
range that yields efficacy without toxicity requires a regimen based on the kinetics
of the active ingredients' availability to target sites.
[0055] Daily dosages for agent (a) or (b) or will, of course, vary depending on a variety
of factors, for example the compound chosen, the particular condition to be treated
and the desired effect. In general, however, satisfactory results are achieved on
administration of agent (a) at daily dosage rates of the order of ca. 0.03-5 mg/kg/day,
particularly 0.1-5 mg/kg/day, e.g., 0.1-2.5 mg/kg/day, as a single dose or in divided
doses. Agents (a) and (b) may be administered by any conventional route, in particular,
enterally, e.g., orally, e.g., in the form of tablets, capsules, drink solutions or
parenterally, e.g., in the form of injectable solutions or suspensions. Suitable unit
dosage forms for oral administration comprise from ca. 0.02-50 mg active ingredient,
usually 0.1-30 mg, e.g., agent (a) or (b), together with one or more pharmaceutically
acceptable diluents or carriers therefore.
[0056] Agent (b) may be administered to a human in a daily dosage range of 0.5-1000 mg.
Suitable unit dosage forms for oral administration comprise from ca. 0.1-500 mg active
ingredient, together with one or more pharmaceutically acceptable diluents or carriers
therefore.
[0057] The administration of a pharmaceutical combination of the invention results not only
in a beneficial effect, e.g., a synergistic therapeutic effect, e.g., with regard
to inhibiting the unregulated proliferation of haematological stem cells or slowing
down the progression of leukemias, such as chronic myeloid leukemia (CML), acute lymphocyte
leukemia (ALL) or acute myeloid leukemia (AML), or the growth of tumors, but also
in further surprising beneficial effects, e.g., less side effects, an improved quality
of life or a decreased morbidity, compared to a monotherapy applying only one of the
pharmaceutically active ingredients used in the combination of the invention.
[0058] A further benefit is that lower doses of the active ingredients of the combination
of the invention can be used, e.g., that the dosages need not only often be smaller
but are also applied less frequently, or can be used in order to diminish the incidence
of side effects. This is in accordance with the desires and requirements of the patients
to be treated.
[0059] Combinations of compounds that inhibit the binding of the Smac protein to IAPs and
taxanes may be combined, independently or together, with one or more pharmaceutically
acceptable carriers and, optionally, one or more other conventional pharmaceutical
adjuvants and administered enterally, e.g., orally, in the form of tablets, capsules,
caplets, etc. or parenterally, e.g., intraperitoneally or intravenously, in the form
of sterile injectable solutions or suspensions. The enteral and parenteral compositions
may be prepared by conventional means.
[0060] The combination of compounds that inhibit the binding of the Smac protein to IAPs
and taxanes can be used alone or combined with at least one other pharmaceutically
active compound for use in these pathologies. These active compounds can be combined
in the same pharmaceutical preparation or in the form of combined preparations "kit
of parts" in the sense that the combination partners can be dosed independently or
by use of different fixed combinations with distinguished amounts of the combination
partners, i.e., simultaneously or at different time points. The parts of the kit of
parts can then, e.g., be administered simultaneously or chronologically staggered,
that is at different time points and with equal or different time intervals for any
part of the kit of parts. Non-limiting examples of compounds which can be cited for
use in combination with the combination of a compounds that inhibit the binding of
the Smac protein to IAPs and taxanes are cytotoxic chemotherapy drugs, such as cytosine
arabinoside, daunorubicin, doxorubicin, cyclophosphamide, VP-16, or imatinib etc.
Further, the combination of a compounds that inhibit the binding of the Smac protein
to IAPs and taxanes could be combined with other inhibitors of signal transduction
or other oncogene-targeted drugs with the expectation that significant synergy would
result.
[0061] The COMBINATION OF THE INVENTION can be a combined preparation or a pharmaceutical
composition.
[0062] Moreover, the present invention relates to a method of treating a warm-blooded animal
having a proliferative disease comprising administering to the animal a COMBINATION
OF THE INVENTION in a quantity which is therapeutically effective against said proliferative
disease.
[0063] Furthermore, the present invention pertains to the use of a COMBINATION OF THE INVENTION
for the treatment of a proliferative disease and for the preparation of a medicament
for the treatment of a proliferative disease.
[0064] Moreover, the present invention provides a commercial package comprising as active
ingredients COMBINATION OF THE INVENTION, together with instructions for simultaneous,
separate or sequential use thereof in the delay of progression or treatment of a proliferative
disease.
[0065] Preferred embodiments of the invention are represented by combinations comprising:
- compound I and paclitaxel;
- compound IV and paclitaxel;
- compound I and docetaxel; and
- compound IV and docetaxel.
[0066] In further aspects, the present inventions provides:
- a combination which comprises:
- (a) a COMBINATION OF THE INVENTION, wherein the active ingredients are present in
each case in free form or in the form of a pharmaceutically acceptable salt or any
hydrate thereof; and, optionally,
- (b) at least one pharmaceutically acceptable carrier; for simultaneous, separate or
sequential use;
- a pharmaceutical composition comprising:
- (a) a quantity which is jointly therapeutically effective against a proliferative
disease of a COMBINATION OF THE INVENTION; and
- (b) at least one pharmaceutically acceptable carrier;
- the use of a COMBINATION OF THE INVENTION for the treatment of a proliferative disease;
- the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for
the treatment of a proliferative disease;
- the use of a COMBINATION OF THE INVENTION wherein the compound that inhibit the binding
of the Smac protein to IAPs is a compound of formula (I); and
- the use of COMBINATION OF THE INVENTION wherein the compound that inhibit the binding
of the Smac protein to IAPs is a compound of formula (IV).
[0067] In particular, the present invention relates to a combination comprising:
- (a) a taxane; and
- (b) a compound that inhibit the binding of the Smac protein to IAPs.
[0068] Moreover, in particular, the present invention relates to a combined preparation,
which comprises:
- (a) one or more unit dosage forms of a taxane; and
- (b) one or more unit dosage forms of a compound that inhibit the binding of the Smac
protein to IAPs.
[0069] Furthermore, in particular, the present invention pertains to the use of a combination
comprising:
- (a) a taxane; and
- (b) a compound that inhibit the binding of the Smac protein to IAPs for the preparation
of a medicament for the treatment of a proliferative disease.
B. Diseases to be treated
[0070] The term "proliferative disease" includes but is not restricted to tumors, psoriasis,
restenosis, sclerodermitis and fibrosis.
[0071] The term hematological malignancy, refers in particular to leukemias, especially
those expressing Bcr-Abl, c-Kit or HDAC (or those depending on Bcr-Abl, c-Kit or HDAC)
and includes, but is not limited to, CML and ALL, especially the Philadelphia chromosome
positive acute lymphocyte leukemia (Ph+ALL), as well as Imatinib-resistant leukemia.
Especially preferred is use of the combinations of the present invention for leukemias,
such as CML, ALL or AML. Most especially preferred is use in diseases which show resistance
to Imatinib and is sold under the name Gleevec
®.
[0072] The term "a solid tumor disease" especially means ovarian cancer, breast cancer,
cancer of the colon and generally the gastrointestinal tract, cervix cancer, lung
cancer, e.g., small-cell lung cancer and non-small-cell lung cancer, head and neck
cancer, bladder cancer, cancer of the prostate or Kaposi's sarcoma.
[0073] The combinations according to the invention, that inhibit the protein kinase activities
mentioned, especially tyrosine protein kinases mentioned above and below, can therefore
be used in the treatment of protein kinase dependent diseases. Protein kinase dependent
diseases are especially proliferative diseases, preferably benign or especially malignant
tumours, e.g., carcinoma of the kidneys, brain, liver, adrenal glands, bladder, breast,
stomach (especially gastric tumors), ovaries, colon, rectum, prostate, pancreas, lungs
(especially SCLC), vagina or thyroid, sarcoma, multiple myeloma, glioblastomas and
numerous tumours of the neck and head, as well as leukemias; especially colon carcinoma
or colorectal adenoma, or a tumor of the neck and head, an epidermal hyperproliferation,
especially psoriasis, prostate hyperplasia, a neoplasia, especially of epithelial
character, preferably mammary carcinoma, or a leukemia. They are able to bring about
the regression of tumours and to prevent the formation of tumour metastases and the
growth of (also micro) metastases. In addition they can be used in epidermal hyperproliferation,
e.g., psoriasis; in prostate hyperplasia; and in the treatment of neoplasias, especially
of epithelial character, e.g., mammary carcinoma. It is also possible to use the combinations
of the present invention in the treatment of diseases of the immune system insofar
as several or, especially, individual tyrosine protein kinases are involved; furthermore,
the combinations of the present invention can be used also in the treatment of diseases
of the central or peripheral nervous system where signal transmission by at least
one tyrosine protein kinase, especially selected from those mentioned specifically,
is involved.
[0074] In CML, a reciprocally balanced chromosomal translocation in hematopoietic stem cells
(HSCs) produces the Bcr-Abl hybrid gene. The latter encodes the oncogenic Bcr-Abl
fusion protein. Whereas Abl encodes a tightly regulated protein tyrosine kinase, which
plays a fundamental role in regulating cell proliferation, adherence and apoptosis,
the Bcr-Abl fusion gene encodes as constitutively activated kinase, which transforms
HSCs to produce a phenotype exhibiting deregulated clonal proliferation, reduced capacity
to adhere to the bone marrow stroma and a reduces apoptotic response to mutagenic
stimuli, which enable it to accumulate progressively more malignant transformations.
The resulting granulocytes fail to develop into mature lymphocytes and are released
into the circulation, leading to a deficiency in the mature cells and increased susceptibility
to infection. ATP-competitive inhibitors of Bcr-Abl have been described which prevent
the kinase from activating mitogenic and anti-apoptotic pathways (e.g., P-3 kinase
and STAT5), leading to the death of the Bcr-Abl phenotype cells and thereby providing
an effective therapy against CML. The combinations of the present invention are thus
especially appropriate for the therapy of diseases related to its overexpression,
especially leukemias, such as leukemias, e.g., CML or ALL.
[0075] In a broader sense of the invention, a proliferative disease includes hyperproliferative
conditions, such as leukemias, hyperplasias, fibrosis (especially pulmonary, but also
other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis;
and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis
following angioplasty. In another aspect the combinations of the present invention
could be used to treat arthritis.
[0076] Combinations of the present invention can also be used to treat or prevent fibrogenic
disorders, such as scleroderma (systemic sclerosis); diseases associated with protein
aggregation and amyloid formation, such as Huntington's disease; inhibition of the
replication of hepatitis C virus and treating hepatitis C virus; treating tumors associated
with viral infection, such as human papilloma virus; and inhibiting viruses dependent
of heat-shock proteins.
[0077] The combinations of the present invention primarily inhibit the growth of blood vessels
and are thus, e.g., effective against a number of diseases associated with deregulated
angiogenesis, especially diseases caused by ocular neovascularisation, especially
retinopathies, such as diabetic retinopathy or age-related macula degeneration; psoriasis;
haemangioblastoma, such as haemangioma; mesangial cell proliferative disorders, such
as chronic or acute renal diseases, e.g., diabetic nephropathy; malignant nephrosclerosis;
thrombotic microangiopathy syndromes or transplant rejection; or especially inflammatory
renal disease, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis;
haemolytic-uraemic syndrome; diabetic nephropathy; hypertensive nephrosclerosis; atheroma;
arterial restenosis; autoimmune diseases; diabetes; endometriosis; chronic asthma;
and especially neoplastic diseases (solid tumors, but also leukemias and other haematological
malignancies), such as especially breast cancer, cancer of the colon, lung cancer
(especially small-cell lung cancer), cancer of the prostate or Kaposi's sarcoma. Combinations
of the present invention inhibit the growth of tumors and are especially suited to
preventing the metastatic spread of tumors and the growth of micrometastases.
[0078] Combinations of the present invention may in particular be used to treat:
- (i) a breast tumor; an epidermoid tumor, such as an epidermoid head and/or neck tumor
or a mouth tumor; a lung tumor, e.g., a small cell or non-small cell lung tumor; a
gastrointestinal tumor, e.g., a colorectal tumor; or a genitourinary tumor, e.g.,
a prostate tumor, especially a hormone-refractory prostate tumor;
- (ii) a proliferative disease that is refractory to the treatment with other chemotherapeutics;
or
- (iii) a tumor that is refractory to treatment with other chemotherapeutics due to
multi-drug resistance.
Example 1
[0079] The combination of Docetaxel with a compound of formula (III) in the ovarian carcinoma
line SKOV3 results in significant synergy
in vitro. Figure 1 indicates anti-proliferative activity of compound of formula (III) alone
(bottom row), Docetaxel alone (most leftward column) and combinations of the two agents
across a dose range.
[0080] Figure 2 is the corresponding isobologram at 70% growth inhibition.
Example 2
[0081] The combination of a compound of formula (III) and Paclitaxel has superior anti-tumor
activity compared to either agent administered as a single agent in the orthotopic
breast cancer model MDA-MB-231. Established tumors were treated for two weeks with
the dose regimens indicated in Figure 2.
Example 3
[0082] Figure 4 indicates anti-proliferative activity of Taxol is dramatically enhanced
by combination with a compound of formula (III) in the melanoma cell line A375. Top
curve shows dose response of Taxol alone in A375 in three day proliferation assay.
Bottom two curves show Taxol dose response in presence of either 6 µM or 12 µM compound
of formula (III).
[0083] The compound of formula (III) has no stand alone activity in A375 (data not shown).
Example 4
[0084] IAP Inhibitor compounds such as LBW242 display single agent activity on a limited
number of tumor cell lines in vitro. To determine whether a larger number of cell
lines are responsive to an IAP Inhibitor in combination with Taxol, Taxol dose response
evaluations are performed in the presence or absence of LBW242 with 10-12 tumor cell
lines representing the following cancers: lung, ovarian, melanoma, pancreatic. The
criteria used for an assignment of combination activity - either additivity or synergy
- is a minimum of a five fold potency shift for the IC50 of Taxol in combination with
LBW242 relative to Taxol alone. Tumor cell lines which are responsive to LBW242 as
a monotherapy such as MDA231 and SKOV3 also exhibit combination activity with Taxol.
In all cancer types tested, tumor cell lines are identified in which the IAP Inhibitor
compound has no single agent activity yet enhances the response to Taxol. Thus, the
range of tumor cell lines sensitive to LBW242 in combination with a cytotoxic agent
is slightly larger than the range responsive as a single agent.
[0085] LBW242, LCJ917, LCP656 and LCL161 are Smac mimetic small molecules with nM affinity
for the BIR3 domain of XIAP and CIAP1. As Inhibitor of Apoptosis Proteins (IAPs) are
thought to protect tumor cells from apoptotic cell death, it was anticipated that
such agents would sensitize tumor cells to apoptotic stimuli. Interestingly, such
agents have anti-proliferative/apoptosis inducing activity as single agents against
a narrow range of tumor cell lines for reasons which remain unclear. To determine
whether the spectrum of tumor cell lines which responded to these agents would be
wider in combination with the cytotoxic drug Taxol, we subject panels of tumor cell
lines representing a number of human cancers to in vitro combination analyses.
Materials and Methods
[0086] MTS Reagent (#G1111; Promega) in PBS, pH 6 - 6.5. Phenazine Methosulfate (PMS) (#P-5812;
Sigma). 96 well tissue culture plates (#3585; Corning Costar). RPMI 1640 cell culture
medium (#22400-071; Invitrogen). Penicillin/Streptomycin (#15140-122; Invitrogen).
Fetal Bovine Serum (#10082-139; Invitrogen). (Note: RPMI 1640+10% FBS + Penicillin/Streptomycin
is "RPMI/10% FBS Complete medium"). 0.25% Trypsin-EDTA (#25200-056; Invitrogen). The
IAP Inhibitor compounds LBW242, LCJ917, LCP656 and LCL161 are dissolved in DMSO at
a concentration of 10 mM and stored at -20°C. Tumor Cell Lines are purchased from
ATCC.
MTS Assay
[0087] Cell proliferation/cell death is analyzed in 72 hr. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,
inner salt (MTS) assays. Tumor cell lines are plated at subconfluent densities in
96 well plate format and allowed to adhere for 12 - 16 hr. Cpds are then added according
to the following schemes: i. Chemotherapeutic agents or cytotoxic cpds (Ctx) are added
alone, in an 8-point/10-fold titration scheme from high to low dose, in triplicate.
ii. IAP-inhibitor (NVP-LBW242) is added alone, at a single fixed dose ( dose determined
in stand alone MTS assays ) in triplicate. iii. Ctx agent (8-point/10-fold scheme)
and LBW242 (single fixed dose) are added together, simultaneously, in triplicate.
Once all dosing is completed, cells are cultured for a further 72 hr. and then assayed
using the MTS format:
Day -1
- 1. Plate cells in RPMI/10% FBS Complete medium. Set-up Time 0 (T.0) and Experimental
(EXP) plates as appropriate for each cell line. Each plate will contain culture medium
(CM) alone (Blank) wells (200ul/well).
- 2. An additional "Blank" plate will contain Blank wells: the center 24 wells will
contain 12 wells with 100 ul CM/well and 12 wells with 110 ul CM/well. All surrounding
wells will contain 200 ul CM/well.
- 3. Trypsinize cells at 37°c/5% CO2 for up to 5', quench the trypsin with CM and then
plate cells onto 96 well plates at 90 ul/well. Seed cells at densities appropriate
for each cell line (appropriate cell densities will yield optimal cell growth which
is reflected in T.0 OD 490 values between 0.3 - 0.8). Add 90 ul CM to 6 Blank wells
on the T.0 plate and 200 ul CM to all surrounding wells. Add 200 ul CM to all outer
wells on Exp plates. Culture plates @ 37°C/ 5% CO2 for 24 (T.0 plate) to 96 hr. (EXP
plates).
Day 0
- 1. Add MTS/PMS reagents to T.0 Plate(s). Mix enough of each reagent (100 ul 500 uM
PMS per 2 ml 333 ug/ml MTS reagent / 96 well plate ) for 20 ul / well. Add 20 ul mixture
to ea. well & incubate plate(s) 2 hr. @ 37°C / 5% CO2. Read OD 490 nm using SoftMax
Pro software on a Molecular Devices (Sunnyvale, CA) Spectrophotometer. Calculate T.0
values for each cell line to be assayed by generating the mean value of the OD 490
nm readings from each cell line's T.0 wells (6/ cell line) and subtracting the mean
OD 490 nm values from Blank wells.
- 2. Dose EXP plate(s) with appropriate Cdps in triplicate in the schemes shown in Fig
5. Incubate plates at 37°C/5% CO2 for 72 hr.
Day 3
- 1. Add MTS/PMS reagents to EXP Plate(s). Mix enough of each reagent (100 ul 500 uM
PMS per 2 ml 333 ug/ml MTS reagent / 96 well plate ) for 20 ul / well. Add 20 ul mixture
to ea. well & incubate plate(s) 2 hr. @ 37°C / 5% CO2. Read OD 490 nm using SoftMax
Pro software on a Molecular Devices Spectrophotometer. MTS Data is generated as described
below:
Calculate % CG by first averaging triplicate results (subtracting blank medium values)
as follows:
Selection of IAP Inhibitor Dose Levels
[0088] IAP Inhibitors are used at a single fixed dose of 10 uM (12 uM in earliest assays)
in lines where compound shows no effect (IC50 > 10 uM) as a single agent.
[0089] IAP Inhibitors are used at a single fixed dose yielding 70 - 80% control cell growth
(%CG) (between IC20 - IC30 dose) in lines where compounds show moderate stand alone
activity (IC50 1 - 10 uM) as a single agent.
[0090] In most cases, fixed doses in specific cell lines are set by generating empirical
data in MTS assays.
Criteria for Call of Combination Activity
[0091] Combinations exhibiting a ≥ 5-fold potency shift in the IC50 dose as compared with
Taxol alone are scored as a combination activity hits provided that under similar
conditions LBW242 by itself did not result in < 70 %CG (IC30).
[0092] True assessment of synergy requires fixed ratio titrations of combination partners
and determination of combination indices. The above criteria do not formally distinguish
between synergy and additivity.
Ovarian Tumor Cell lines:
[0093]
Fig. 5 Taxol + 100 nM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in OVCAR-4
Fig. 6 Taxol + 1 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in OVCAR-4
Fig. 7 Taxol + 10 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combinations in TOV 21 G
Fig. 8 Taxol + 80 nM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combinations in SKOV-3
Melanoma Cancer Cell Lines:
[0094]
Fig. 9 Taxol + 10 uM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in SKMEL-2
Fig. 10 Taxol + 10 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in SKMEL-2
Fig. 11 Taxol + 10 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in MEWO
Fig. 12 Taxol + 10 uM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in A375
Fig. 13 Taxol + 1 uM N-[1-Cyclohexyl-2-(2-{2-[(4-fluoro-phenyl)-methyl-amino]-pyridin-4-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide
Combination in A375
Fig. 14 Taxol + 6 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in A375
Fig. 15 Taxol + 10 uM N-(1-Cyclohexyl-2-{2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in A375
Fig. 16 Taxol + 10 uM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in A375
Fig. 17 Taxol + 1 uM N-[1-Cyclohexyl-2-(2-{2-[(4-fluoro-phenyl)-methyl-amino]-pyridin-4-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide
Combination in A375
Fig. 18 Taxol + 10 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in A375
Fig. 19 Taxol + 10 uM N-(1-Cyclohexyl-2-{2-[5-(4-fluoro-phenoxy)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in A375
Lung Tumor Cell Lines:
[0095]
Fig. 20 Taxol + 10 uM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in NCl-H2030
Fig. 21 Taxol + 2 uM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in NCl-H23
Fig. 22 Taxol + 0.5 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in SK-LU-1
Fig. 23 Taxol + 7 uM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in NCl-H441
Fig. 24 Taxol + N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in NCl-H441
Fig. 25 Taxol + 4 uM N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
Combination in A-427
Fig. 26 Taxol + 10 uM N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamide
Combination in A-427
1. A pharmaceutical combination comprising:
(a) a compound that inhibit the binding of the Smac protein to Inhibitor of Apoptosis
Proteins (IAPs) of formula (I)
wherein
R1 is H, C1-C4alkyl, C1-C4alkenyl, C1-C4alkynyl or C3-C10cycloalkyl, which are unsubstituted or substituted;
R2 is H, C1-C4alkyl, C1-C4alkenyl, C1-C4alkynyl or C3-C10cycloalkyl, which are unsubstituted or substituted;
R3 is H, -CF3, -C2F5, C1-C4alkyl, C1-C4alkenyl, C1-C4alkynyl, -CH2-Z, wherein Z is H, -OH, F, Cl, -CH3, -CF3, -CH2Cl, -CH2F or -CH2OH, or
R2 and R3, together with the nitrogen, form a het ring;
R4 is C1-C16straight- or branched-alkyl, C1-C16alkenyl, C1-C16alkynyl or -C3-C10cycloalkyl, -(CH2)1-6Z1, -(CH2)0-6aryl and -(CH2)0-6het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted,
wherein
Z1 is -N(R8)-C(O)-C1-C10alkyl, -N(R8)-C(O)-(CH2)1-6C3-C7cycloalkyl, -N(R8)-C(O)-(CH2)0-6phenyl, -N(R8)-C(O)-(CH2)1-6het, -C(O)-N(R9)(R10), -C(O)-O-C1-C10alkyl, -C(O)-O-(CH2)1-6C3-C7cycloalkyl, -C(O)-O-(CH2)0-6phenyl, -C(O)-O-(CH2)1-6het, -O-C(O)C1-C10alkyl, -O-C(O)-(CH2)1-6C3-C7cycloalkyl, -O-C(O)-(CH2)0-6phenyl, -O-C(O)-(CH2)1-6het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; and
het is a 5- to 7-membered heterocyclic ring containing 1-4 heteroatoms selected from
N, O and S, or an 8- to 12-membered fused ring system including at least one 5- to
7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O,
and S, which heterocyclic ring or fused ring system is unsubstituted or substituted
on a carbon or nitrogen atom,
wherein
R8 is H, -CH3, -CF3, -CH2OH or -CH2Cl;
R9 and R10 are each independently H, C1-C4alkyl, C3-C7cycloalkyl, -(CH2)1-6C3-C7cycloalkyl, -(CH2)0-6phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or
R9 and R10, together with the nitrogen, form het;
R5 is H, C1-C10alkyl, aryl, phenyl, C3-C7cycloalkyl, -(CH2)1-6C3-C7cycloalkyl, -C1-C10alkylaryl, -(CH2)0-6C3-C7cycloalkyl-(CH2)0-6phenyl, -(CH2)0-4CH-((CH2)1-4phenyl)2, -(CH2)0-6CH(phenyl)2, -indanyl, -C(O)-C1-C10alkyl, -C(O)-(CH2)1-6C3-C7-cycloalkyl, -C(O)-(CH2)0-6phenyl, -(CH2)0-6C(O)-phenyl, -(CH2)0-6het, -C(O)-(CH2)1-6het, or
R5 is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents
are unsubstituted or substituted; and
U is as shown in formula (II):
wherein
n is 0-5;
X is -CH or N;
Ra and Rb are independently an O, S or N atom or C0-C8alkyl, wherein one or more of the carbon atoms in the alkyl chain may be replaced
by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted
or substituted;
Rd is selected from:
(a) -Re - Q - (Rf)p(Rg)q; or
(b) Ar1-D- Ar2,
wherein
p and q are independently 0 or 1;
Re is C1-C8alkyl or alkylidene and
Re which may be unsubstituted or substituted;
Q is N, O, S, S(O), or S(O)2;
Ar1 and Ar2 are substituted or unsubstituted aryl or het;
Rf and Rg are each independently H, -C1-C10alkyl, C1-C10alkylaryl, -OH, -O-C1-C10alkyl, -(CH2)0-6C3-C7cycloalkyl, -O-(CH2)0-6aryl, phenyl, aryl, phenyl-phenyl, -(CH2)1-6het, -O-(CH2)1-6het, -OR11, -C(O)-R11, -C(O)-N(R11)(R12), -N(R11)(R12), -S-R11, -S(O)-R11, -S(O)2-R11, -S(O)2-NR11R12, -NR11-S(O)2-R12, S-C1-C10alkyl, aryl-C1-C4alkyl, het-C1-C4-alkyl, wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted,
-SO2-C1-C2alkyl, -SO2-C1-C2alkylphenyl, -O-C1-C4alkyl, or
Rg and Rf form a ring selected from het or aryl;
D is -CO-, -C(O)-C1-C7alkylene or arylene, -CF2-, -O-, -S(O)r, where r is 0-2,
1,3-dioaxolane or C1-C7alkyl-OH, where alkyl, alkylene or arylene may be unsubstituted or substituted with
one or more halogens, OH, -O-C1-C6alkyl, -S-C1-C6alkyl or -CF3, or
D is -N(Rh), wherein Rh is H, C1-C7alkyl (unsubstituted or substituted), aryl, -O(C1-C7cycloalkyl) (unsubstituted or substituted), C(O)-C1-C10alkyl, C(O)-Co-C10alkyl-aryl, C-O-C1-C10alkyl, C-O-Co-C10alkyl-aryl or SO2-C1-C10-alkyl, SO2-(Co-C10-alkylaryl);
Rc is H, or
Rc and Rd may together form a cycloalkyl or het, where if Rd and Rc form a cycloalkyl
or het, R
5 is attached to the formed ring at a C or N atom;
R
6, R
7, R'
6 and R'
7 are each independently H, -C
1-C
10alkyl, -C
1-C
10alkoxy, aryl-C
1-C
10alkoxy, -OH, -O-C
1-C
10alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -O-(CH
2)
0-6aryl, phenyl, -(CH
2)
1-6het, -O-(CH
2)
1-6het, -OR
11, -C(O)-R
11, -C(O)-N(R
11)(R
12), -N(R
11)(R
12), -S-R
11, -S(O)-R
11, -S(O)
2-R
11, -S(O)
2-NR
11R
12, -NR
11-S(O)
2-R
12, wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted; and R
6, R
7, R'
6 and R'
7 can be united to form a ring system,
wherein
R
11 and R
12 are independently H, C
1-C
10alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -(CH
2)
0-6(CH)
0-1(aryl)
1-2, -C(O)-C
1-C
10alkyl, -C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-O-(CH
2)
0-6aryl, -C(O)-(CH
2)
0-6O-fluorenyl, -C(O)-NH-(CH
2)
0-6aryl, -C(O)-(CH
2)
0-6aryl, -C(O)-(CH
2)
1-6het, -C(S)-C
1-C
10alkyl, -C(S)-(CH
2)
1-
6C
3-C
7cycloalkyl, -C(S)-O-(CH
2)
0-6aryl, -C(S)-(CH
2)
0-6O-fluorenyl, -C(S)-NH-(CH
2)
0-6aryl, -C(S)-(CH
2)
0-6aryl, -C(S)-(CH
2)
1-6het, wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted, or
R
11 and R
12 are a substituent that facilitates transport of the molecule across a cell membrane,
or
R
11 and R
12, together with the nitrogen atom, form het,
wherein
the alkyl substituents of R
11 and R
12 may be unsubstituted or substituted by one or more substituents selected from C
1-C
10alkyl, halogen, OH, -O-C
1-C
6alkyl, -S-C
1-C
6alkyl or -CF
3;
substituted cycloalkyl substituents of R
11 and R
12 are substituted by one or more substituents selected from a C
1-C
10alkene, C
1-C
6alkyl, halogen, OH, -O-C
1-C
6alkyl, -S-C
1-C
6alkyl or -CF
3; and
substituted phenyl or aryl of R
11 and R
12 are substituted by one or more substituents selected from halogen, hydroxy, C
1-C
4alkyl, C
1-C
4alkoxy, nitro, -CN, -O-C(O)-C
1-C
4alkyl and -C(O)-O-C
1-C
4aryl;
or pharmaceutically acceptable salts thereof
or (IV)
wherein
R
1 is H;
R
2 is H, C
1-C
4alkyl, which is unsubstituted or substituted by one or more substituents selected
from halogen, -OH, -SH, -OCH
3, -SCH
3, -CN, -SCN and nitro;
R
3 is H, -CF
3, -C
2F
5, -CH
2-Z, wherein Z is H, -OH, F, Cl, -CH
3, -CF
3, -CH
2Cl, -CH
2F or -CH
2OH, or
R
2 and R
3, together with the nitrogen, form a C
3-C
6heteroaliphatic ring;
R
4 is C
1-C
16straight-chain alkyl, C
3-C
10branched-chain alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -(CH
2)
1-6Z
1, -(CH
2)
0-6phenyl and -(CH
2)
0-6het, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or substituted,
wherein
Z
1 is -N(R
9)-C(O)-C
1-C
10alkyl, -N(R
9)-C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -N(R
9)-C(O)-(CH
2)
0-6phenyl, -N(R
9)-C(O)-(CH
2)
1-6het, -C(O)-N(R
10)(R
11), -C(O)-O-C
1-C
10alkyl, -C(O)-O-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-O-(CH
2)
0-6phenyl, -C(O)-O-(CH
2)
1-6het, -O-C(O)-C
1-C
10alkyl, -O-C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -O-C(O)-(CH
2)
0-6phenyl, -O-C(O)-(CH
2)
1-6het, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or substituted,
wherein
R
9 is H, -CH
3, -CF
3, -CH
2OH or CH
2Cl;
R
10 and R
11 are each independently H, C
1-C
4alkyl, C
3-C
7cycloalkyl, -(CH
2)
1-6C
3-C
7cycloalkyl, -(CH
2)
0-6phenyl, wherein the alkyl, cycloalkyl and phenyl substituents are unsubstituted or
substituted, or
R
10 and R
11, together with the nitrogen, are het;
het is a 5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected
from N, O and S, or an 8- to 12-membered fused ring system including at least one
5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from
N, O and S, which heterocyclic ring or fused ring system is unsubstituted or substituted
on a carbon atom by halogen, hydroxy, C
1-C
4alkyl, C
1-C
4alkoxy, nitro, -O-C(O)-C
1-C
4alkyl or -C(O)-O-C
1-C
4alkyl or on a nitrogen by C
1-C
4alkyl, -O-C(O)-C
1-C
4alkyl or -C(O)-O-C
1-C
4alkyl;
X is CH or N;
R
5 is H, C
1-C
10alkyl, C
3-C
7cycloalkyl, -(CH
2)
1-6C
3-C
7cycloalkyl, -C
1-C
10alkyl-aryl, -(CH
2)
0-6C
3-C
7cycloalkyl-(CH
2)
0-6phenyl, -(CH
2)
0-4CH-((CH
2)
1-4phenyl)
2, -(CH
2)
0-6CH(phenyl)
2, -C(O)-C
1-C
10alkyl, -C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-(CH
2)
0-6phenyl, -(CH
2)
1-6het, -C(O)-(CH
2)
1-6het, or
R
5 is a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents
are unsubstituted or substituted;
R
6 is H, methyl, ethyl, -CF
3, -CH
2OH or -CH
2Cl, or
R
5 and R
6, together with the nitrogen, are het;
R
7 and R
8 are cis relative to the acyl substituent at the one position of the ring and are
each independently H, -C
1-C
10alkyl, -OH, -O-C
1-C
10alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -O-(CH
2)
0-6aryl, phenyl, -(CH
2)
1-6het, -O-(CH
2)
1-6het, -N(R
12)(R
13), -S-R
12, -S(O)-R
12, -S(O)
2-R
12, -S(O)
2-NR
12R
13, wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted,
wherein
R
12 and R
13 are independently H, C
1-C
10alkyl, -(CH
2)
0-6C
3-C
7cycloalkyl, -(CH
2)
0-6(CH)
0-1(aryl)
1-2, -C(O)-C
1-C
10alkyl, -C(O)-(CH
2)
1-6C
3-C
7cycloalkyl, -C(O)-O-(CH
2)
0-6aryl, -C(O)-(CH
2)
0-6O-fluorenyl, -C(O)-NH-(CH
2)
0-6aryl, -C(O)-(CH
2)
0-6aryl, -C(O)-(CH
2)
1-6het, wherein the alkyl, cycloalkyl and aryl substituents are unsubstituted or substituted;
or a substituent that facilitates transport of the molecule across a cell membrane,
or
R
12 and R
13, together with the nitrogen, are het; and
aryl is phenyl or naphthyl which is unsubstituted or substituted;
n is 0, 1 or 2; and
(b) at least one taxane.
2. A method for treating or preventing a proliferative disease in a subject in need thereof,
comprising co-administration to said subject of a therapeutically effective amount
of at least one taxane and a compound that inhibit the binding of the Smac protein
to IAPs of formula (I) or (IV) according to claim 1.
3. A pharmaceutical combination according to Claim 1, for use in a method according to
Claim 2.
4. A pharmaceutical combination according to Claim 1, for use in the preparation of a
medicament for use in a method according to Claim 2.
5. A pharmaceutical combination according to Claim 1, wherein agent a) is
N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-
c]pyridin-1-yl-ethyl]-2-methylamino-propionamide of formula (III):
6. A pharmaceutical combination according to Claim 1, wherein agent b) is selected from
Paclitaxel, docetaxel, vinorelbine and the epothilones and combinations thereof.
7. A method for treating a proliferative disease comprising administering a combination
of a taxane and a compound that inhibit the binding of the Smac protein to IAPs of
formula (I) or (IV).
8. A method for treating a proliferative disease comprising administering a combination
of a taxane and a compound selected from N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamide of formula (III) and pharmaceutically
acceptable salts thereof.
9. A method for treating a proliferative disease comprising administering a combination
of a taxane and a compound that inhibit the binding of the Smac protein to IAPs of
formula (I) or (IV), wherein the taxane is selected from paclitaxel and docitaxel,
and combinations thereof.
10. A method for treating a proliferative disease selected from breast, ovarian and lung
tumors comprising administering a combination of a taxane and a compound that inhibit
the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs) of formula
(I) or (IV).
11. A method for treating a proliferative disease selected from breast, ovarian and lung
tumors comprising administering a combination of a taxane and a compound selected
from N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamide of formula (III) and pharmaceutically
acceptable salts thereof.
12. A pharmaceutical combination according to Claim 1, wherein the compound a) is N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
(LCL161).
13. A pharmaceutical combination according to Claim 12, wherein the taxane is paclitaxel
or docetaxel.
14. A pharmaceutical combination according to claim 12 or 13 for use in the treatment
of proliferative disease.
15. A pharmaceutical combination for use in the treatment of proliverative disease according
to claim 14, wherein the proliferative disease is
(i) a breast tumor; an epidermoid tumor; a lung tumor; a gastrointestinal tumor; or
a genitourinary tumor;
(ii) a proliferative disease that is refractory to the treatment with other chemotherapeutics;
or
(iii) a tumor that is refractory to treatment with other chemotherapeutics due to
multi-drug resistance.